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Guidance for Industry
Nonclinical Evaluation of Late Radiation Toxicity of Therapeutic
Radiopharmaceuticals
DRAFT GUIDANCE
This guidance document is
being distributed for comment purposes only.
Comments and suggestions regarding this draft
document should be submitted within 90 days of publication in the
Federal Register of the notice announcing the availability
of the draft guidance. Submit comments to the Division of Dockets
Management (HFA-305), Food and Drug Administration, 5630 Fishers
Lane, rm. 1061, Rockville, MD 20852. All comments should be
identified with the docket number listed in the notice of
availability that publishes in the Federal Register.
For questions regarding this draft document
contact Adebayo Laniyonu or Renee Tyson at 301-827-7510.
U.S. Department of Health and Human
Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
June 2005
Pharmacology and Toxicology
This
draft guidance, when finalized, will represent the Food and Drug
Administration’s (FDA’s) current thinking on this topic. It
does not create or confer any rights for or on any person and
does not operate to bind FDA or the public. You can use an
alternative approach if the approach satisfies the requirements
of the applicable statutes and regulations. If you want to
discuss an alternative approach, contact the FDA staff
responsible for implementing this guidance. If you cannot
identify the appropriate FDA staff, call the appropriate number
listed on the title page of this guidance.
The objective of this guidance is to provide
recommendations to industry for designing nonclinical late
radiation toxicity studies to determine potential late radiation
effects of therapeutic radiopharmaceutical agents. The purpose of
conducting nonclinical late radiation toxicity studies is to help
minimize the risk of late-occurring radiation toxicities in
clinical studies of therapeutic radiopharmaceuticals. Because
there are other CDER guidances available for conventional
nonclinical safety studies,
this guidance focuses solely on late radiation safety concerns
that are unique to therapeutic radiopharmaceuticals. These unique
safety concerns result from the risk of irreversible late
radiation toxicity when these agents deliver high doses of
ionizing radiation to normal organs.
This guidance is not intended for
radiobiologicals (e.g., radiolabeled monoclonal antibodies). The
exclusion of radiolabeled biologics is based on the lack of an
established animal model for human biodistribution and the
associated residence time of investigational monoclonal antibodies
or other biologics. This guidance is also not intended for
diagnostic radiopharmaceuticals whose low doses are not expected
to elicit late radiation toxic effects.
FDA’s guidance documents, including this
guidance, do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency’s current thinking on a
topic and should be viewed only as recommendations, unless
specific regulatory or statutory requirements are cited. The use
of the word should in Agency guidances means that something
is suggested or recommended, but not required.
Therapeutic radiopharmaceuticals are
typically administered systemically to treat cancer. For cancer
therapy with curative intent, the radiation absorbed doses
delivered by therapeutic radiopharmaceuticals are comparable to
those delivered with external beam radiotherapy (XRT) and are
orders of magnitude higher than doses delivered by diagnostic
radiopharmaceuticals. At therapeutic doses of radiation, the late
radiation toxicities commonly associated with XRT (renal,
pulmonary, neurologic, late bone marrow failures, and others) can
also be seen. With XRT, if the total dose given to an organ is
less than its tolerance dose, the probability of symptomatic late
radiation toxicity to that organ will be minimal (Perez and Brady
et al. 2004). This type of toxicity should not be confused with
the radiation-induced secondary malignancies for which the risk is
known and accepted as unavoidable. The tolerance doses of most
human organs for conventionally fractionated XRT (2 Gy once per
day, 5 days per week) are known, and are routinely used to direct
the safe administration of XRT. In the FDA’s experience, however,
there are few clinical data from which to estimate organ tolerance
doses for therapeutic radiopharmaceuticals.
Organ tolerance doses for systemically
administered therapeutic radiopharmaceuticals can differ
significantly from the published tolerance doses for
conventionally fractionated high dose rate XRT. With XRT, the
dose received by an organ is determined by the geometric
arrangement of the radiation beams. Organs in close proximity to
the tumor are at greatest risk. In the case of systemically
administered radiopharmaceuticals, the dose received by each organ
is determined by the pharmacokinetics and biodistribution of the
radiopharmaceutical agent. Available radiation dosimetry software
programs (e.g., Medical Internal Radiation Dose (MIRDOSE) and
Organ Level Internal Dose Assessment (OLINDA)) can be used to
provide only rough estimates of radiation absorbed doses received
by specific organs following administration of therapeutic
pharmaceuticals. The accuracy of such estimates is determined by
the accuracy of the pharmacokinetic data that are used in the
model.
The organ tolerance doses for XRT are based
on conventionally fractionated high dose rate therapy.
Fractionation allows for repair of radiation damage between
fractions, whereas therapeutic radiopharmaceuticals usually
deliver a single dose of radiation at a low dose rate, where
damage and repair of that damage occur simultaneously as competing
processes. Therefore, organ tolerance doses for systemically
administered therapeutic radiopharmaceuticals are not directly
comparable to those for XRT. In fact, late radiation toxicity has
been observed with therapeutic radiopharmaceuticals at estimated
organ doses that were below the XRT tolerance doses for the target
organs (Giralt and Bensinger et al. 2003). The recently described
entity of low dose hypersensitivity may account for the
discrepancy as could anatomic concentration of isotope not
captured in the MIRDOSE (Joiner and Marples et al. 2001; Marples
and Wouters et al. 2004).
Irreversible late radiation toxicities in the
kidneys and bladder were observed in clinical trials with two
therapeutic radiopharmaceutical agents where administered doses
were estimated based upon external beam tolerance dose limits. In
one study of radiopharmaceutical treatment of multiple myeloma, 30
out of 83 patients developed renal dysfunction. Seven patients
developed severe thrombotic microangiopathy (TMA) that required
renal dialysis, and five of the seven patients died (Giralt and
Bensinger et al. 2003). In a second clinical study of 36 patients
receiving radiopharmaceutical therapy for somatostatin
receptor-positive tumors, five patients developed TMA; three of
whom progressed to end stage renal failure (Moll and Nickeleit et
al. 2001). These toxicities were not immediately recognized as
complications of the treatment because they did not begin to occur
until at least 3 months after radiopharmaceutical therapy. This
type of delayed onset is typical of late radiation toxicity.
Therefore, there is a need to gain additional
knowledge in this area to support the safe administration of
therapeutic radiopharmaceuticals to humans. Because studies in
humans would be unethical, the best means to gain insight into
this issue is by conducting nonclinical late radiation toxicity
studies. These studies will aid in identifying organs at risk and
establish a margin of safety for late radiation toxicity. As a
result, these studies will help to minimize the risk of
late-occurring radiation toxicities in clinical studies of
therapeutic radiopharmaceuticals.
Ionizing radiation causes injury to cells and
tissues by damaging nuclear DNA (Hall 2000), although non-DNA
targets are now described (Coppes and Meter et al. 2005). Most
damaged cells will continue to function normally until they die
while attempting to undergo mitosis. Thus the time frame in which
radiation injury becomes clinically apparent is determined in part
by cell turnover time (Rubin 1984). In organs with a rapid cell
turnover (early reacting normal tissue) (e.g., bone marrow,
epidermis, small intestine, and oropharyngeal mucosa), symptoms of
radiation injury (e.g., bone marrow failure, desquamation, nausea,
vomiting and diarrhea, and oral mucositis) will appear within days
to weeks of an acute dose of radiation. Radiation injury to these
organs is called early or acute radiation toxicity and is often
self-limiting and reversible. However, in organs with a slow cell
turnover rate (late responding normal tissue) (e.g., the brain,
spinal cord, heart, lungs, liver, kidneys, bone, and bladder),
symptoms of radiation injury (e.g., brain necrosis, paralysis,
pericardial and myocardial fibrosis with left ventricular failure,
interstitial pneumonitis and pulmonary fibrosis, liver or kidney
failure, osteoradionecrosis, and hemorrhagic cystitis) do not
occur until after a latency period of several months to years
during which relatively normal organ function continues.
Radiation injury to these organs is referred to as late radiation
toxicity and is usually progressive and irreversible (Yaes 1992;
Tubiana and Dutreix et al. 1990; Fajardo and Berthrong et al.
2001).
Since acute radiation toxicity becomes
apparent within a short time period after administration,
proximity in time to radiation exposure can be used as an
important criterion in determining whether the radiopharmaceutical
is the cause of a particular complication or adverse effect. Such
toxicities will become apparent early in a clinical trial and the
study can be revised or terminated, as appropriate. In contrast,
late radiation toxicity in organs such as the kidneys, liver, or
central nervous system (CNS) will not become apparent until months
or years after treatment, necessitating longer term follow-up of
treated patients.
With XRT, radiation injury is limited to
organs within the radiation beams. With radiopharmaceutical
therapy, the risk of radiation injury to an organ is determined by
the organ’s radiosensitivity and by the concentration
time-activity curve of the agents in that organ or at a specific
anatomical target. For example, late radiation effects can occur
if the kidneys receive a significant radiation absorbed dose from
radiopharmaceuticals that are removed from the systemic
circulation by glomerular filtration. The kidneys are known to
have a relatively low radiation tolerance dose (23 Gy for
conventionally fractionated XRT); therefore, late radiation
nephritis may be a dose-limiting toxicity for many therapeutic
radiopharmaceuticals. Although the bladder tolerance dose is
considerably higher (65 Gy), hemorrhagic cystitis can occur as a
late effect unless the bladder is adequately irrigated to reduce
residency time.
For treatment with therapeutic
radiopharmaceuticals with curative intent, radiation absorbed
doses comparable to doses delivered by XRT must be delivered to
the tumor. Since similarly high doses may be unavoidably
delivered to normal tissue, radiation toxicities commonly
associated with XRT may also be seen with radiopharmaceutical
therapy. Because the prescribed radioactivity is given with a
very small mass dose of the carrier drug, radiation toxicity,
rather than pharmacological toxicity associated with the cold (nonradioactive)
drug substance (formulation), is often dose-limiting. In the
past, nonclinical toxicity studies have been performed mainly with
the cold formulation. Although these studies have usually shown
that the no observable adverse effect levels (NOAELs) are many
times the clinical mass dose, such studies assess the toxicity of
the cold formulation only. Therefore, to assess the risk of late
radiation toxicity in humans, it is necessary to perform late
radiation toxicity studies in animals. Such studies may allow the
sponsor to:
·
Perform controlled experiments that are not ethically feasible in
humans.
·
Identify organs at risk for late radiation toxicity.
·
Establish a NOAEL for late-occurring, irreversible radiation
effects in an appropriate animal species, to help select the
clinical doses.
·
Compare the biological effects and tolerance doses of radiation
delivered with radiopharmaceutical therapy to those of radiation
delivered by XRT in specific organs.
·
Examine the pathologic changes and possible mechanism of injury.
·
Distinguish the toxicity of radiopharmaceutical therapy from that
of other concomitant therapies.
·
Determine the amount of organ sparing that could be obtained by
fractionating the radiopharmaceutical dose.
There are challenges associated with the
design and conduct of nonclinical late radiation toxicity
studies. Therapeutic doses of radiopharmaceuticals require the
administration of large amounts of radioactivity. The animals and
animal waste will be radioactive, requiring radiation precautions
to protect personnel and the general public. Precautions will
also be necessary for the disposal of radioactive waste. Despite
these challenges, such studies have been conducted, and are
recommended to optimize dosing and thus ensure safe clinical
trials and patient care. Before initiating late radiation
toxicity studies, the sponsor should discuss the specifics of the
study design with representatives of the Division of Medical
Imaging and Radiopharmaceutical Drug Products and consider the
following factors.
Late radiation toxicity studies performed for
the safety evaluation of a radiopharmaceutical drug product should
be conducted in accordance with pre-existing requirements under
the regulations for good laboratory practices (21 CFR part 58) and
the Animal Welfare Act (7 U.S.C. 2131 et seq.).
When choosing
a species, the sponsor should take into consideration the
similarity in dosimetry, biodistribution, and pharmacokinetic
profile of the radiopharmaceutical in the selected species and in
humans. Suitable animal models to
study late radiation toxicity are available. In published
studies, rats (Moulder and Fish et al. 1998; Moulder and
Fish 1989; Molteni and Moulder et al. 2000)
and dogs (Prescott and Hoopes et al. 1990;
McChesney and Gillette et al. 1989)
have been shown to develop late radiation nephropathy and
pulmonary fibrosis after external beam irradiation.
Radiation-induced myocardial fibrosis has been shown to occur in
rabbits (Fajardo and Stewart 1973)
and dogs (Gavin and
Gillette 1982).
We recommend that the animal studies be
scheduled to facilitate the conduct of clinical trials, including
the selection of appropriate safety monitoring methods based on
findings in such studies. To select the most appropriate species,
human dosimetry and pharmacokinetic data using tracer doses should
be obtained before initiation of the late radiation toxicity
study. Ideally, the studies should be completed before the start
of phase 2 dose escalation clinical trials because late radiation
toxicity may not be seen in the first dose cohort until after the
entire trial has been completed. In certain cases, a phase 2
clinical study can be initiated before complete submission of data
from the late radiation toxicity study based on a risk-benefit
analysis. However, we will evaluate the appropriateness of this
approach on a case-by-case basis.
The study
design should capture acute (occurring within the first few weeks
after irradiation) as well as delayed (occurring after a prolonged
latency) radiation effects. Clinically, late radiation toxicity
is not observed until at least several months to years following
the radiotherapy. In animals, late radiation toxicity usually
occurs on a shorter timescale than in humans. For example, the
latent period for radiation nephritis in rats ranges from 3 to 7
months. In dogs, renal dysfunction is observed by 10 months.
Therefore, to obtain a reasonable estimate of the incidence of
specific adverse effects, animals should be monitored for late
radiation toxicity for at least 1 year post-dosing. Study
duration of less than 1 year should be justified.
The preclinical study design should closely
mimic the design of the anticipated clinical studies including the
injected amount of radioactivity (mCi/m2), number of
doses, frequency of dosing, and dosing interval. If both single
and fractionated dosing will be studied in clinical trials, a
two-arm study design evaluating late radiation toxicity after
single as well as fractionated dosing may be necessary. If
planned radiation doses in humans will require hematopoietic
growth factor support or bone marrow rescue, it may be necessary
to support or rescue the irradiated animals so that they will
survive comparable doses to allow for late radiation toxicity
observations.
Parameters that should be monitored are
similar to those evaluated in expanded single or repeat-dose
toxicity studies. These include clinical observations, food
consumption, body weight, ophthalmologic examination, hematology,
clinical chemistry, urinalysis, and post-mortem investigations
(e.g., necropsy, organ weights, macroscopic and microscopic
examinations).
Late radiation toxicity studies in animals
should include at least four dose levels to identify the NOAEL and
dose-related mild-to-severe late radiation toxicity. The study
should also include the cold formulation (ideally, the cold
isotope equivalent to the highest mass dose) as a control group to
distinguish specific radiation effects from potential
pharmacological effects of the cold formulation. The
dose-limiting toxicities will be severe but are usually reversible
(e.g., acute radiation toxicity related to the gastrointestinal
tract, bone marrow). Therefore, the highest dose selected should
produce acute radiation toxicity. This dose should be at least
twice the maximum planned human dose or radiation tolerance dose
for the critical organ (TD5/5 external beam radiation) identified
as a possible dose-limiting factor in clinical studies. The
dose-multiples should be expressed in terms of body surface area (mCi/m2)
and radiation absorbed dose to the critical organs, when critical
organs have been identified. The number of animals in each group
should be sufficient to ensure survival of an adequate number to
perform proper analysis at the completion of study.
Hematology, urinalysis, and clinical
chemistries should be performed pre-dosing, 2 weeks post-dosing,
then once every 3 months afterward and at termination. In
addition to a standard battery of hematology and clinical
chemistry parameters, the study should also include the assessment
of relevant biomarkers, if available, to identify late radiation
toxicity for the target organ. For example, urinary
glutathione-S-transferase isoenzyme levels can be monitored in
addition to blood urea nitrogen and creatinine levels as markers
for renal injury. It is recommended that the study design be
developed in consultation with the FDA to ensure that appropriate
long-term toxicity indices are monitored.
Necropsy, including organ weights and
macroscopic examination of various organs, should be performed for
all animals in the study, including those that died during the
study observation period. Detailed histopathologic/microscopic
evaluation should be performed at termination.
Late radiation toxicity has been observed
where doses of radiopharmaceuticals were determined based on
external beam organ tolerance dose limits. Therefore, there is
clearly a need to gain additional knowledge in this area to
support the safe administration of these products. Because
studies in humans would be unethical, the best means to gain
insight into the potential irreversible late radiation toxicity
with these products is by conducting nonclinical toxicity
studies. These studies will aid in identifying at-risk organs,
establish a margin of safety for late radiation toxicity, quantify
potential organ sparing when dose fractionation is used, and
compare organ tolerance doses for radiopharmaceutical therapy to
tolerance doses for fractionated external beam treatment.
Late radiation toxicity protocols should be
submitted to the Agency for review before the studies are
initiated. Ideally, radiation toxicity studies in animals should
be completed and analyzed before phase 2 dose escalation toxicity
studies are initiated in patients. Until we have a better
understanding of tolerance doses for radiopharmaceutical therapy,
the safest way to proceed is to prescribe doses in mCi/m2
to individualize patient doses by body surface area. Since
pharmacokinetic parameters for some of these agents have been
known to vary significantly from patient to patient, before any
patient is treated, biodistribution and pharmacokinetic data
should be obtained for that individual patient using quantitative
gamma camera imaging with diagnostic doses of the therapeutic
agent where possible. These data should be used to estimate
radiation absorbed doses to each individual patient’s critical
organs using MIRDOSE-3 or OLINDA (or other adequate) dosimetry
software. For patients who would receive unusually high doses to
critical organs, it may be necessary to decrease the injected
activity, or exclude the patient from the study.
Coppes, RP, A Meter, SP Latumalea, AF Roffel,
HH Kampinga, 2005, Defects in Muscarinic Receptor-Coupled Signal
Transduction in Isolated Parotid Gland Cells After in Vivo
Irradiation: Evidence for a Non-DNA Target of Radiation, Br J
Cancer, 92:539-46.
Fajardo, L, M Berthrong, R Anderson, 2001,
Radiation Pathology, Oxford University Press, Oxford England.
Fajardo, LF and JR Stewart, 1973,
Pathogenesis of Radiation-Induced Myocardial Fibrosis, Lab Invest,
29:244-257.
Gavin, PR, and EL Gillette, 1982, Radiation
Response of the Canine Cardiovascular System, Radiat Res,
90:489-500.
Giralt, S, W Bensinger, M Goodman, D Podoloff,
J Eary et al., 2003, 166Ho-DOTMP Plus Melphalan
Followed by Peripheral Blood Stem Cell Transplantation in Patients
with Multiple Myeloma: Results of Two Phase 1-2 Trials, Blood,
102:2684-2691.
Hall, EJ, 2000, Radiobiology for the
Radiologist (5th edition), Lippincott Williams & Wilkins,
Philadelphia Pa.
Joiner, MC, B Marples, P Lambin, SC Short, I
Turesson, 2001, Low-Dose Hypersensitivity: Current Status and
Possible Mechanisms, Int J Radiat Oncol Biol Phys, 49:379-89.
Marples, B, BG Wouters, SJ Collis, AJ
Chalmers, MC Joiner, 2004, Low-Dose Hyper-Radiosensitivity: A
Consequence of Ineffective Cell Cycle Arrest of Radiation-Damaged
G2-Phase Cells, Radiat Res, 161:247-55.
McChesney, SL, EL Gillette, BE Powers, 1989,
Response of the Canine Lung to Fractionated Irradiation:
Pathologic Changes and Isoeffect Curves, Int J Radiat Oncol Biol
Phys, 16(1):125-32.
Moll, S, V Nickeleit, J Mueller-Brand, F
Brunner, H Maecke, M Mihatsch, 2001, A New Cause of Renal
Thrombotic Microangiopathy: Yttrium 90-DOTATOC Internal
Radiotherapy, Am J Kidney Dis, 37:847-851.
Molteni, A, JE Moulder, EF Cohen, WF Ward, BL
Fish et al., 2000, Control of Radiation-Induced Pneumopathy and
Lung Fibrosis by Angiotensin-Converting Enzyme Inhibitors and an
Angiotensin II Type 1 Receptor Blocker, Int J Radiat Biol,
76(4):523-532.
Moulder, JE and BL Fish, 1989, Late Toxicity
of Total Body Irradiation with Bone Marrow Transplantation in a
Rat Model, Int J Radiat Oncol Biol Phys, 16 (6):1501-9.
Moulder, JE, BL Fish, EP Cohen, 1998,
Angiotensin II Receptor Antagonists in the Treatment and
Prevention of Radiation Nephropathy, Int J Radiat Biol,
73(4):415-21.
Perez, CA, LW Brady, EC Halperin, RK Schmidt-Ullrich,
(eds), 2004, Principles and Practice of Radiation Oncology (4th
edition), Lippincott Williams & Wilkins, Philadelphia Pa.
Prescott, DM, PJ Hoopes, DE Thrall, 1990,
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Rubin, P, 1984, The Franz Buschke Lecture:
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Yaes, R, 1992, Radiation Damage to the
Kidney, Advances in Radiation Biology, 15:1-35.
Acute Radiation Syndrome
—
The
symptoms, when taken together, characterize a person suffering from
the effects of intense radiation. The effects occur within hours or
days.
Dose Fractionation
—
A
method of administering therapeutic radiation in which relatively
small doses are given daily or at longer intervals.
Early Effects (of radiation exposure)
—
Effects that appear within 60 days of an acute exposure.
Late Effects (of radiation exposure)
—
Effects that appear 60 days or more following an acute exposure.
Radiation Absorbed Dose
—
The energy imparted to matter by ionizing radiation per unit mass of
irradiated material at the place of interest. In SI units, the unit
of radiation absorbed dose is the Gray (Gy), which is 1 J/Kg. One
Gy equals 100 rads.
Radionuclide
—
Any
radioactive isotope of an element.
Radiosensitivity
—
Relative susceptibility of cells, tissues, organs, organisms, or any
living substance to the injurious action of radiation.
Radiosensitivity and its antonym, radioresistance, are currently
used in a comparative sense, rather than in an absolute one.
Therapeutic Radiopharmaceutical
— A radiopharmaceutical drug product or radiobiological that is
intended for use in the treatment of cancer in humans and that
contains a radioactive isotope which exhibits spontaneous
disintegration of unstable nuclei with the emission of nuclear
radiation. The isotopes used in therapeutic radiopharmaceuticals
are usually beta emitters whereas the isotopes used in diagnostic
radiopharmaceuticals are gamma emitters. Therapeutic
radiopharmaceuticals are given in much higher activities and deliver
much higher radiation absorbed doses than diagnostic
radiopharmaceuticals.
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Date created: June 17, 2005 |
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